This application is the national phase of international application PCT/GB97/03379 filed Dec. 5, 1997 which designated the U.S.
The present invention relates to stabilised compositions containing a metal complex of a cyclic thiohydroxamic acid or a 1-hydroxy-2-pyrrolidinthione and to improved antibacterial activity.
EP 249328 discloses metal complexes of cyclic thiohydroxamic acids and 1-hydroxy-2-pyrrolidinthiones and their use as industrial biocides. These metal complexes may also be used in personal care formulations as disclosed in EP 498636.
It has now been found that when these metal complexes are used in the presence of certain chemical compounds which act as ligands for the metal, the metal is removed at least in part from the metal complex and this results in a reduction in microbiological activity and/or a reduction in chemical stability, especially under acidic conditions. It has now been found that the metal complexes of cyclic thiohydroxamic acids (hereinafter xe2x80x98CTHAxe2x80x99) and the metal complexes of 1-hydroxy-2-pyrrolidinthiones (hereinafter xe2x80x98HPTxe2x80x99) may be stabilised by adding a salt of the metal and/or a metal complex of the metal derived from a ligand which is weaker than the CTHA or HPT. In many instances the metal complex of the CTHA and HPT exhibit increased antimicrobial activity in the presence of a salt of the metal, especially where the metal is zinc.
According to the invention there is provided a composition comprising
(a) a metal complex of a compound of formula 1 
xe2x80x83wherein
A is xe2x80x94CR2xe2x80x94 or xe2x80x94CRxe2x95x90;
B is xe2x80x94CR2xe2x80x94, xe2x80x94CRxe2x95x90 or  greater than Cxe2x95x90NR; or
A and B or B and D together form a 6-membered fused hydrocarbon ring;
D is sulphur, xe2x80x94NRxe2x80x94, xe2x80x94CR2xe2x80x94 or xe2x80x94CR=;
R is C1-6-hydrocarbyl optionally substituted by halogen or two groups R together with the carbon atom to which they are attached form a 6-membered ring; and
(b) a salt of the metal and/or a metal complex of the metal obtainable from a ligand which is weaker than the compound of formula 1.
When R is hydrocarbyl, it may be phenyl. However, R is preferably alkyl, which may be linear or branched but is preferably linear. Examples of these alkyl groups are ethyl, isopropyl, n-butyl, tert-butyl, amyl, hexyl and especially methyl.
When A and B or B and D form a ring, the ring is preferably cyclohexenyl, cyclohexyl and especially phenyl.
When R is substituted by halogen, the substituent may be iodine, bromine or preferably chlorine.
When two groups R together with the carbon atom to which they are attached form a ring, the ring is preferably cyclohexyl.
The metal forming the complex with the compound of formula 1 may be any of the metals in groups 1b, 2a, 2b, 3a or 8 of the Periodic Table according to Mendeleef as published, for example, on the inside cover of the Handbook of Chemistry and Physics, The Chemical Rubber Company. It is preferred that the metal is from group 2b and that it is especially zinc.
The metal salt which is component (b) may be the salt of an inorganic or organic acid. In this context, a metal oxide is considered to be a salt of an inorganic acid. Preferred inorganic acids are hydrohalic acids, especially hydrochloric acid, nitric acid and sulphuric acid. It is particularly preferred that the salt is that of an organic acid or a metal oxide. Preferred organic acids are monocarboxylic acids, particularly those containing not greater than 10 and especially not greater than 6 carbon atoms excluding the xe2x80x94COOH group. Examples of organic acids are propionic and especially acetic acid.
When component (b) is a metal complex, it is preferably obtainable from an organic compound wherein the ligand(s) is a hydroxy group. The organic compound which forms a complex with the metal has a MW which is preferably not greater than 300, more preferably not greater than 250 and especially not greater than 200.
One preferred class of compounds of formula 1 is a cyclic thiohydroxamic acid wherein D is sulphur. Examples are
3-hydroxy-4-methylthiazol-2(3H)-thione,
3-hydroxy-4-phenylthiazol-2(3H)-thione,
3-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2(3H)-thione,
5,5-dimethyl-1-hydroxy-4-imino-3-phenylimidazolidine-2-thione,
1-hydroxy-4-imino-3-phenyl-2-thiono-1,3-diazaspiro[4,5]decane,
1-hydroxy-5-methyl-4-phenylimidazoline-2-thione,
4,5-dimethyl-3-hydroxythiazol-2(3H)-thione,
4-ethyl-3-hydroxy-5-methylthiazol-2(3H)-thione,
4-(4-chlorophenyl)-3-hydroxythiazol-2(3H)-thione and
3-hydroxy-5-methyl-4-phenylthiazol-2(3H)-thione.
Another preferred class of compounds of formula 1 is a 1-hydroxy-2-pyrrolidinthione wherein D is xe2x80x94CR2xe2x80x94 or xe2x80x94CR=. Examples are
2-hydroxy-2,3-dihydro-1H-isoindol-1-thione,
1-hydroxy-2-pyrrolidinthione and
5,5-dimethyl-1-hydroxy-2-pyrrolidinthione.
Particularly useful effects have been obtained when component (a) is the 2:1 zinc complex of 3-hydroxy-4-methylthiazol-2(3H)-thione and component (b) is zinc acetate, zinc chloride or zinc oxide.
The composition according to the invention may be a mixture of component (a) and component (b) in solid form or it may further comprise a liquid medium when the composition comprises a dispersion of component (a) in the liquid medium containing component (b).
The liquid medium is preferably water.
The dispersion may also contain other adjuvants which are conventionally used to aid the dispersion of particulate solids in a liquid medium. These adjuvants include dispersants and compounds capable of forming a structured network of the liquid medium which aids the suspension of particulate solids (hereinafter xe2x80x9cStructuring Agentxe2x80x9d).
The dispersant may be non-ionic, anionic, cationic or amphoteric. Preferred dispersants are non-ionic and are preferably ethoxylated fatty alcohols especially C12-18-alkanols containing from 5 to 20 ethylene oxide units.
Preferred Structuring Agents are cellulose derivatives, naturally occurring clays and especially polysaccharide thickeners. Examples are hydroxyethylcellulose, Bentonite and Zanthan gum.
Component (b) may be soluble in or dispersible in the liquid medium but is preferably soluble.
The dispersion may be made by any means known to the art and may be made by grinding or milling component (a) in the presence of an attrition aid such as glass beads in order to reduce the particle size. The particle size of component (a) is preferably reduced below 20 xcexc, more preferably below 10 xcexc and especially to below 3 xcexc. The fine particle of component (a) may then be added to component (b) and the liquid medium. Alternatively, components (a) and (b) may be ground or milled together and then added to the liquid medium. It is preferred, however, to grind or mill component (a) in the liquid medium containing component (b).
The amount of component (b) relative to component (a) may be just sufficient to provide enhanced microbiological activity and/or a stabilising effect but is preferably present in larger amounts. Preferably the weight ratio of component (b) to component (a) is between 5:1 and 1:5, more preferably between 3:1 and 1:2 and especially between 2:1 and 1:1.
The amount of component (a) in the dispersion is from 1 to 30% relative to the total weight of the dispersion. Preferably the amount of component (a) is not less than 3% and especially not less than 5% relative to the total weight of the dispersion. It is also preferred that the amount of component (a) is not greater than 20%, more preferably not greater than 15% and especially not greater than 10% relative to the total weight of the dispersion.
The amount of dispersant depends on the amount of component (a) but is generally between 5% and 200% based on the weight of component (a). Preferably the amount of dispersant is not greater than 100% and especially not greater than 50% based on the weight of component (a).
The amount of Structuring Agent, when present, depends on the total weight of the dispersion and is preferably not less than 0.05%, more preferably not less than 0.1% and especially not less than 0.2% based on the total weight of the dispersion. It is also preferred that the amount of Structuring Agent is not greater than 1% and especially not greater than 0.5% based on the total weight of dispersion.
The pH value of the dispersion can be from pH3 to pH10 but is preferably not less than 5, more preferably not less than 6 and especially not less than 6.5. It is also preferred that the pH is not greater than 9 and especially not greater than 8.
When the pH value of the dispersion needs to be adjusted this may be carried out by adding any appropriate organic or inorganic acid or base. However, when component (b) is an inorganic or organic metal salt it is advantageous to use the same acid as that providing the metal salt when reducing the pH of the dispersion.
When the dispersion contains a Structuring Agent, the viscosity of the dispersion is preferably not less than 1000, more preferably not less than 1200 and especially not less than 1500 centipoise as measured by Brookfield viscometer using Spindle No. 2 and a rotational speed of 10 rpm at 20xc2x0 C. The viscosity is also preferably not greater than 4,000, more preferably not greater than 3,500 and especially not greater than 3,000 centipoise at 20xc2x0 C.
The composition may contain additional biologically active compounds especially where it is desirable to increase the spectrum of activity. In some instances an enhanced activity is obtained.
Examples of other antimicrobial compounds which may be used, together with the composition are quaternary ammonium compounds such as N,N-diethyl-N-dodecyl-N-benzylammonium chloride; N,N-dimethyl-N-octadecyl-N-(dimethylbenzyl)ammonium chloride; N,N-dimethyl-N,N-didecylammonium chloride; N,N-dimethyl-N,N-didodecylammonium chloride; N,N,N-trimethyl-N-tetradecylammonium chloride; N-benzyl-N,N-dimethyl-N-(C12-C18 alkyl)ammonium chloride; N-(dichlorobenzyl)-N,-N-dimethyl-N-dodecylammonium chloride; N-hexadecylpyridinium chloride; N-hexadecylpyridinium bromide; N-hexadecyl-N,N,N-trimethylammonium bromide; N-dodecylpyridinium chloride; N-dodecylpyridinium bisulphate; N-benzyl-N-dodecyl-N,N-bis(beta-hydroxy-ethyl)ammonium chloride; N-dodecyl-N-benzyl-N,N-dimethylammonium chloride; N-benzyl-N,N-dimethyl-N-(C12-C18 alkyl) ammonium chloride; N-dodecyl-N,N-dimethyl-N-ethylammonium ethylsulphate; N-dodecyl-N,N-dimethyl-N-(1-naphthylmethyl)ammonium chloride; N-hexadecyl-N,N-dimethyl-N-benzylammonium chloride; N-dodecyl-N,N-dimethyl-N-benzylammonium chloride and 1-(3-chloroallyl)-3,5,7-triaza-1-azonia-adamantane chloride; urea derivatives such as 1,3-bis(hydroxymethyl)-5,5-dimethylhydantoin; bis(hydroxymethyl)urea; 3-(3,4-dichlorophenyl)-1,1-dimethylurea; 3-(4-isopropylphenyl)-1,1-dimethylurea; tetrakis (hydroxymethyl)-acetylene diurea; 1-(hydroxymethyl)-5,5-dimethylhydantoin and imidazolidinylurea; amino compounds such as 1,3-bis(2-ethyl-hexyl)-5-methyl-5-aminohexahydro-pyrimidine; hexamethylenetetramine; 1,3-bis(4-aminophenoxy)propane; and 2-[(hydroxymethyl)-amino]ethanol; imidazole derivatives such as 1[2-(2,4-dichloro-phenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole; 2-(methoxycarbonyl-amino)-benzimidazole; nitrile compounds such as 2-bromo-2-bromomethyl-glutaronitrile, 1,2-dibromo-2,4-dicyanatobutane, 2-chloro-2-chloro-methylglutaronitrile; 2,4,5,6-tetra-chloroisophthalodinitrile; thiocyanate derivatives such as methylene(bis)thiocyanate; tin compounds or complexes such as tributyltinoxide, chloride, naphthoate, benzoate or 2-hydroxybenzoate; isothiazolin-3-ones such as 4,5-trimethylene-4-isothiazolin-3-one, 2-methyl-4,5-trimethylene-4-isothiazolin-3-one, 2-methylisothiazolin-3-one, 5-chloro-2-methyl-isothiazolin-3-one, benzisothiazolin-3-one, 2-n-butylbenzisothiazolin-3-one, 2-n-hexylbenzisothiazolin-3-one, 2-(2-ethylbutyl)benzisothiazolin-3-one, 2-(2-phenylethyl) benzisothiazolin-3-one, 2-(2-ethylhexyl)benzisothiazolin-3-one; 2-methylbenzisothiazolin-3-one, 2-octylisothiazolin-3-one, 4,5-dichloro-2-octylisothiazolin-3-one; thiazole derivatives such as 2-(thiocyanomethylthio)-benzthiazole and mercaptobenzthiazole; nitro compounds such as tris(hydroxymethyl)nitromethane; 5-bromo-5-nitro-1,3-dioxane and 2-bromo-2-nitropropane-1,3-diol; iodine compounds such as iodo propynyl butyl carbamate and tri-iodo allyl alcohol; aldehydes and derivatives such as glutaraldehyde (pentanedial), p-chlorophenyl-3-iodopropargyl, formaldehyde and glyoxal; amides such as chloracetamide; N,N-bis(hydroxymethyl)chloracetamide; N-hydroxymethylchloracetamide and dithio-2,2-bis(benzmethylamide); guanidine derivatives such as poly (hexamethylenebiguanide) and 1,6-hexamethylene-bis[5-(4-chlorophenyl)biguanide]; thiones such as 3,5-dimethyltetrahydro-1,3,5-2H-thiodiazine-2-thione; triazine derivatives such as hexahydrotriazine and 1,3,5-tri-(hydroxyethyl)-1,3,5-hexahydrotriazine, 6-chloro-2,4-diethyl-amino-s-triazine and 4-cyclopropylamino-2-methylthio-6-t-butylamino-s-triazine; oxazolidine and derivatives thereof such as bis-oxazolidine; furan and derivatives thereof such as 2,5-dihydro-2,5-dialkoxy-2,5-dialkylfuran; carboxylic acids and the salts and esters thereof such as sorbic acid and 4-hydroxybenzoic acid and their salts and esters; phenol and derivatives thereof such as 5-chloro-2-(2,4-dichlorophenoxy)phenol; thio-bis(4-chlorophenol) and 2-phenylphenol, 2,4,4xe2x80x2-trichloro-2xe2x80x2-hydroxydiphenylether; sulphone derivatives such as diiodomethyl-paratolyl sulphone; 2,3,5,6-tetrachloro-4-(methylsulphonyl) pyridine and hexachlorodimethyl sulphone; thioamides such as dimethyidithiocarbamate and its metal complexes, ethylenebisdithiocarbamate and its metal complexes, and 2-mercapto-pyridine-N-oxide and its metal complexes.
The composition and dispersion of the present invention is microbiologically active and can be used to protect any medium against microbiological degradation. The medium may be an industrial medium such as a latex, paint, cooling tower water, paper mill liquor, sealant, pipe joint tapes, adhesive, drilling mud or cutting fluid. The medium may also be any personal care formulation, especially those disclosed in EP 498,636 and especially shampoo formulations. The medium may also be a solid surface such as wood, leather and particularly any surface associated with the preparation of foodstuffs.